Many genetic mutations have been identified that cause human muscular dystrophies, but the mechanisms of cellular damage remain poorly understood for these diseases. In many cases a similar mutation in different individuals cause different degrees of disability. Understanding the molecular basis of the common pathophysiology and the factors that contribute to individual variance will be important for managing and treating muscular dystrophies. Our broad and long-term objective is to identify the molecular mechanisms that mediate the pathologic response to the causative mutation in myotonic. Our specific aims will: (Aim 1) Use a model system of skeletal muscle differentiation and tissue samples from individuals with myotonic dystrophy to identify defects in the molecular regulation of gene transcription in caused by the CUG repeat containing RNA. (Aim 2) Determine whether variable patterns of CpG methylation in the region of the DM 1 locus contribute to the highly variable penetrance of the disease. The significance of this proposal is that it will determine the molecular basis of gene expression changes associated with myotonic dystrophy and the contribution of methylation to the clinical phenotype. These studies will provide a basis for therapeutic intervention.